Individual variation in reactivity to stress is a fundamental feature of mammalian species and is expressed at a variety of biological levels, e.g., behavioral, endocrinological, autonomic, etc. It has furthermore been implicated in the etiology of a variety of disorders including heart disease, hypertension and a number of psychiatric conditions. Two rat strains, the Maudsley Reactive (MR) and the Maudsley Non-Reactive (MNR), provide unique tools for the analysis of variations in stress-reactivity. A constellation of differences has been described in the MR and MNR strains which indicates that alterations in stress-reactivity permeate many biological levels, e.g., behavioral differences in aversive situations, differences in endocrine response to stress and alterations in the reactivity of the central and peripheral noradrenergic systems and cardiovascular systems to stress. The cluster of differences seen in the Maudsley strains could be the result of genetic linkage of relevant alleles, functional association between the different systems or fortuituous fixation of unrelated genetic systems. To analyze the relationship between the various characteristics in the Maudsley strains (the progenitor strains) a battery of recombinant-inbred (RI) strains (the RXNRA strains) has been developed. Traits that are fortuituously associated in the progenitor strains are randomized among RI strains and thus the RXNRA strains provide excellent tools for the detection and analysis of traits that are functionally associated or genetically linked in the progenito strains. In this project we will begin to analyze the relationship between the various expression of stress-reactivity by focusing on the potential role of the peripheral sympathetic nervous system (PSNS) in the strain differences in cardiovascular function. Biochemical measures will be taken in the RXNRA strains which reflect both the pre- and post-synaptic state of the PSNS; in addition, we will obtain cardiovascular measurements and biochemical indices reflecting sympathomedullary activity under resting conditions and in response to stress. Pharmacological interventions will also be carried out using compounds which mimic or antagonize the PSNS in specific receptor populations to further evaluate the role of the PSNS in strain differences in cardiovascular function. By examining the association between these various characteristics among the RXNRA strains we will determine the nature of their association in the progenitor strains.